The Centers for Disease Control and Prevention (“CDC”) estimates that nearly two million infections annually involve resistant bacteria which result in at least 23,000 deaths every year, and notes the potentially catastrophic consequences of inaction. See Antibiotic resistance threats in the United States, 2013, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, pp. 1-113 (2013) at 6. Due to the increasing prevalence of drug resistance in bacterial strains, compromised in particular through overuse, antibiotic treatments are losing efficacy and potency in fighting infections, and, according to the Infectious Disease Society of America, at least ten new synthetic antibacterial drugs need to enter the market by the year 2020 in order to maintain the current quality of healthcare. See Spellberg, B. Antibiotic Resistance: Promoting Critically Needed Antibiotic Research and Development and Appropriate Use (“Stewardship”) of these Precious Drugs, Testimony of the Infectious Diseases Society of America (IDSA), Before the House Committee on Energy and Commerce Subcommittee on Health, Jun. 9, 2010.
Multidrug-resistant Mycobacterium tuberculosis, methicillin-resistant and vancomycin-resistant Staphylococcus aureus, and blaNDM-1/blaKPC Klebsiella pneumoniae are significant global threats. See Fischbach, M. A.; Walsh, C. T. Science, 325:1089-1093 (2009). Therefore, it is urgent that new antibiotics, especially with new mechanisms of action, are discovered to meet the challenge of drug-resistant strains. See World Health Organization (2013) Global Tuberculosis Report, 308.
The bacterial enzyme, N-succinyl-L,L-diaminopimelic acid desuccinylase (“DapE”) is a protein involved in the lysine and diaminopimelic acid (“Dap”) biosynthetic pathway, and is critical for the synthesis of the bacterial cell wall. See Gillner, et al. Bioorg. Med. Chem. Lett., 2009, 19, 6350-635; Scapin, et al. Adv. Enzymol. Relat. Areas Mol. Biol., 1998, 72, 279-32; Gilvarg, et al. J. Biol. Chem., 1959, 234, 2955-2959. Small molecules that are able to block DapE activity are expected to be toxic to bacteria, allowing them to function effectively as antibiotics. Traditional DapE inhibitors, however, are suboptimal because they contain thiol moieties. The thiol moieties are prone to oxidation and also exhibit promiscuous selectivity because they often bind tightly to any zinc-containing enzyme. Also, at least one thiol-containing antimicrobial, captopril, was found to be independent of DapE inhibition. See Creus et al., Bioinorg. Chem. Appl., 2011, 306465.
Metalloproteins account for nearly half the proteins in biology, but in contrast to the more ubiquitous mononuclear enzymes, di-nuclear metalloproteins constitute a large class of these proteins, yet we currently lack effective methods of inhibiting these enzymes for the development of new therapies.
β-Lactam antibiotics are the most commonly used antibacterial agents, and growing resistance to these drugs is a concern. Metallo-β-lactamases (“MBLs”) are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs conferring resistance to the bacteria. New Delhi metallo-β-lactamase 1 (“NDM-1”) is a zinc-dependent metallohydrolase found in bacteria that confers resistance to commonly-administered antibiotics, including penicillins, cephalosporins, and carbapenems. See Rolain, J. M.; Parola, P.; Cornaglia, G. Clinical Microbiology and Infection 2010, 16, 1699-1701; PLoS One 2011, 6, e24621; J. Am. Chem. Soc. 2014, 136, 7273-7285. Horizontal gene transfer has enabled the blaNDM-1 gene to spread between species, facilitating the development of multi-drug resistant bacterial strains. Id. Bacteria carrying the blaNDM-1 gene have been found on all continents, and consequently, NDM-1 has gained international attention as a clinically relevant pharmaceutical target. Id. Known inhibitors of MBLs, such as thiol-containing inhibitors, are prone to oxidation and challenges with selectivity due to the thiol moiety. See Li et al., Bioorganic & Medicinal Chemistry 24:386-389 (2014). As such, drug development efforts of NDM-1 have proven ineffective due to a lack of effective inhibitors. See Rolain et al., Clinical Microbiology and Infection, 16:1699-1701(2010).
Therefore, new compounds capable of inhibiting DapE and MBLs, such as NDM-1 are greatly needed. See, e.g, Christopeit et al., Bioorganic & Medicinal Chemistry 24:2947-2943 (2016); Zhang et al., ChemMedChem Communications 9:2445-2448 (2014), Feng et al., Bioorganic & Medicinal Chemistry 22:5185-5189 (2012), Yang et al., ACS Medicinal Chemistry Letters 6:455-460 (2015).